Bacterial infections pose a serious public health concern, especially when an infectious disease has a multidrug resistant causative agent. Such multidrug resistant bacteria can compromise the clinical utility of major chemotherapeutic antimicrobial agents. Drug and multidrug resistant bacteria harbor several distinct molecular mechanisms for resistance. Bacterial antimicrobial agent efflux pumps represent a major mechanism of clinical resistance. The major facilitator superfamily (MFS) is one of the largest groups of solute transporters to date and includes a significant number of bacterial drug and multidrug efflux pumps. We review recent work on the modulation of multidrug efflux pumps, paying special attention to those transporters belonging primarily to the MFS.
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Structural comparison of bacterial multidrug efflux pumps of the major facilitator superfamily.
The biological membrane is an efficient barrier against water-soluble substances. Solute transporters circumvent this membrane barrier by transporting water-soluble solutes across the membrane to the other sides. These transport proteins are thus required for all living organisms. Microorganisms, such as bacteria, effectively exploit solute transporters to acquire useful nutrients for growth or to expel substances that are inhibitory to their growth. Overall, there are distinct types of related solute transporters that are grouped into families or superfamilies. Of these various transporters, the major facilitator superfamily (MFS) represents a very large and constantly growing group and are driven by solute- and ion-gradients, making them passive and secondary active transporters, respectively. Members of the major facilitator superfamily transport an extreme variety of structurally different substrates such as antimicrobial agents, amino acids, sugars, intermediary metabolites, ions, and other small molecules. Importantly, bacteria, especially pathogenic ones, have evolved multidrug efflux pumps which belong to the major facilitator superfamily. Furthermore, members of this important superfamily share similar primary sequences in the form of highly conserved sequence motifs that confer useful functional properties during transport. The transporters of the superfamily also share similarities in secondary structures, such as possessing 12- or 14-membrane spanning α-helices and the more recently described 3-helix structure repeat element, known as the MFS fold. The three-dimensional structures of bacterial multidrug efflux pumps have been determined for only a few members of the superfamily, all drug pumps of which are surprisingly from Escherichia coli. This review briefly summarizes the structural properties of the bacterial multidrug efflux pumps of the major facilitator superfamily in a comparative manner and provides future directions for study.
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- Award ID(s):
- 1301346
- NSF-PAR ID:
- 10082841
- Date Published:
- Journal Name:
- Trends in Cell & Molecular Biology
- Volume:
- 10
- ISSN:
- 0972-8449
- Page Range / eLocation ID:
- 131-140
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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